US10807953B2 - Processes and intermediates for the preparation of Pimavanserin - Google Patents
Processes and intermediates for the preparation of Pimavanserin Download PDFInfo
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- US10807953B2 US10807953B2 US16/423,810 US201916423810A US10807953B2 US 10807953 B2 US10807953 B2 US 10807953B2 US 201916423810 A US201916423810 A US 201916423810A US 10807953 B2 US10807953 B2 US 10807953B2
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- pimavanserin
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- RKEWSXXUOLRFBX-UHFFFAOYSA-N pimavanserin Chemical compound C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1 RKEWSXXUOLRFBX-UHFFFAOYSA-N 0.000 title claims abstract description 108
- 229960003300 pimavanserin Drugs 0.000 title claims abstract description 94
- 238000000034 method Methods 0.000 title claims abstract description 53
- 230000008569 process Effects 0.000 title claims abstract description 48
- 239000000543 intermediate Substances 0.000 title abstract description 30
- 238000002360 preparation method Methods 0.000 title description 64
- 150000003839 salts Chemical class 0.000 claims abstract description 73
- 150000001875 compounds Chemical class 0.000 claims description 194
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 48
- 238000004519 manufacturing process Methods 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- ALOCUZOKRULSAA-UHFFFAOYSA-N 1-methylpiperidin-4-amine Chemical compound CN1CCC(N)CC1 ALOCUZOKRULSAA-UHFFFAOYSA-N 0.000 claims description 3
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 claims description 3
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 238000006268 reductive amination reaction Methods 0.000 claims description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical group [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 24
- 238000003786 synthesis reaction Methods 0.000 abstract description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 110
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- 238000006243 chemical reaction Methods 0.000 description 80
- 239000000243 solution Substances 0.000 description 68
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 67
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 47
- 238000003756 stirring Methods 0.000 description 46
- 239000011541 reaction mixture Substances 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 40
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 38
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- 239000000047 product Substances 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 239000013078 crystal Substances 0.000 description 29
- 238000004128 high performance liquid chromatography Methods 0.000 description 29
- -1 2-methylpropan-oxy Chemical group 0.000 description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- 229940125904 compound 1 Drugs 0.000 description 28
- 239000002904 solvent Substances 0.000 description 27
- 239000000203 mixture Substances 0.000 description 25
- 0 [1*]C1=CC=C(CNC(=O)N2C=CN=C2)C=C1 Chemical compound [1*]C1=CC=C(CNC(=O)N2C=CN=C2)C=C1 0.000 description 24
- PLYWEOOWONUOBN-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine Chemical compound C1CN(C)CCC1NCC1=CC=C(F)C=C1 PLYWEOOWONUOBN-UHFFFAOYSA-N 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 24
- 238000000634 powder X-ray diffraction Methods 0.000 description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- ULMCAXBKXGWXFM-UHFFFAOYSA-N N-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine dihydrochloride Chemical compound Cl.Cl.CN1CCC(CC1)NCc1ccc(F)cc1 ULMCAXBKXGWXFM-UHFFFAOYSA-N 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 210000003739 neck Anatomy 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000007832 Na2SO4 Substances 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 9
- HUUPVABNAQUEJW-UHFFFAOYSA-N 1-methylpiperidin-4-one Chemical compound CN1CCC(=O)CC1 HUUPVABNAQUEJW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- HLVFKOKELQSXIQ-UHFFFAOYSA-N 1-bromo-2-methylpropane Chemical compound CC(C)CBr HLVFKOKELQSXIQ-UHFFFAOYSA-N 0.000 description 8
- QWMUMFXFUCDJJI-UHFFFAOYSA-N 4-(2-methylpropoxy)benzonitrile Chemical compound CC(C)COC1=CC=C(C#N)C=C1 QWMUMFXFUCDJJI-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- JBVKKHDTYSDPHA-UHFFFAOYSA-N [4-(2-methylpropoxy)phenyl]methanamine Chemical compound CC(C)COC1=CC=C(CN)C=C1 JBVKKHDTYSDPHA-UHFFFAOYSA-N 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
- 229940125782 compound 2 Drugs 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- 239000002002 slurry Substances 0.000 description 8
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 7
- DLJXEPWUMZTZKU-UHFFFAOYSA-N 4-(2-methylpropoxy)benzamide Chemical compound CC(C)COC1=CC=C(C(N)=O)C=C1 DLJXEPWUMZTZKU-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 150000002466 imines Chemical class 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 5
- QXOHCQDAWAPCKS-UHFFFAOYSA-N C(C(C)C)OC1=CC=C(CNC(=O)N2C=NC=C2)C=C1 Chemical compound C(C(C)C)OC1=CC=C(CNC(=O)N2C=NC=C2)C=C1 QXOHCQDAWAPCKS-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 5
- 229910000564 Raney nickel Inorganic materials 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- BHKUKNJDPIWLRY-UHFFFAOYSA-N [4-(2-methylpropoxy)phenyl]methanamine;hydrochloride Chemical compound Cl.CC(C)COC1=CC=C(CN)C=C1 BHKUKNJDPIWLRY-UHFFFAOYSA-N 0.000 description 5
- DWPIWDIFYXPDHX-UHFFFAOYSA-N [4-(2-methylpropoxy)phenyl]methanol Chemical compound CC(C)COC1=CC=C(CO)C=C1 DWPIWDIFYXPDHX-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000005580 one pot reaction Methods 0.000 description 5
- 238000005192 partition Methods 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 4
- PWASYRSZCSTUIW-UHFFFAOYSA-N 4-(2-methylpropoxy)benzaldehyde Chemical compound CC(C)COC1=CC=C(C=O)C=C1 PWASYRSZCSTUIW-UHFFFAOYSA-N 0.000 description 4
- AEKVBBNGWBBYLL-UHFFFAOYSA-N 4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1 AEKVBBNGWBBYLL-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000012948 isocyanate Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- RGSULKHNAKTFIZ-CEAXSRTFSA-N pimavanserin tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1.C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1 RGSULKHNAKTFIZ-CEAXSRTFSA-N 0.000 description 4
- 238000001144 powder X-ray diffraction data Methods 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- FMCAFXHLMUOIGG-JTJHWIPRSA-N (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-JTJHWIPRSA-N 0.000 description 3
- FAUVLYMBDOUYNO-UHFFFAOYSA-N (4-nitrophenyl) N-[(4-fluorophenyl)methyl]-N-(1-methylpiperidin-4-yl)carbamate Chemical compound CN1CCC(CC1)N(CC1=CC=C(F)C=C1)C(=O)OC1=CC=C(C=C1)[N+]([O-])=O FAUVLYMBDOUYNO-UHFFFAOYSA-N 0.000 description 3
- BPILZXNFTZZYJJ-UHFFFAOYSA-N 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene Chemical compound CC(C)COC1=CC=C(CN=C=O)C=C1 BPILZXNFTZZYJJ-UHFFFAOYSA-N 0.000 description 3
- JDIIGWSSTNUWGK-UHFFFAOYSA-N 1h-imidazol-3-ium;chloride Chemical compound [Cl-].[NH2+]1C=CN=C1 JDIIGWSSTNUWGK-UHFFFAOYSA-N 0.000 description 3
- ZNJRONVKWRHYBF-UHFFFAOYSA-N 2-[2-[2-(1-azatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-7-yl)ethenyl]-6-methylpyran-4-ylidene]propanedinitrile Chemical compound O1C(C)=CC(=C(C#N)C#N)C=C1C=CC1=CC(CCCN2CCC3)=C2C3=C1 ZNJRONVKWRHYBF-UHFFFAOYSA-N 0.000 description 3
- APXLSLWSMWRTTL-UHFFFAOYSA-N 2-[4-(2-methylpropoxy)phenyl]acetic acid Chemical compound CC(C)COC1=CC=C(CC(O)=O)C=C1 APXLSLWSMWRTTL-UHFFFAOYSA-N 0.000 description 3
- ZCRMFKLUOGRCQX-UHFFFAOYSA-N 3-[[4-(2-methylpropoxy)phenyl]methyl]-1,4,2-dioxazol-5-one Chemical compound C(C(C)C)OC1=CC=C(CC2=NOC(O2)=O)C=C1 ZCRMFKLUOGRCQX-UHFFFAOYSA-N 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000006241 alcohol protecting group Chemical group 0.000 description 3
- 125000002877 alkyl aryl group Chemical group 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 231100001261 hazardous Toxicity 0.000 description 3
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- 238000003828 vacuum filtration Methods 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- SDTORDSXCYSNTD-UHFFFAOYSA-N 1-methoxy-4-[(4-methoxyphenyl)methoxymethyl]benzene Chemical compound C1=CC(OC)=CC=C1COCC1=CC=C(OC)C=C1 SDTORDSXCYSNTD-UHFFFAOYSA-N 0.000 description 2
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 description 2
- CVNOWLNNPYYEOH-UHFFFAOYSA-N 4-cyanophenol Chemical compound OC1=CC=C(C#N)C=C1 CVNOWLNNPYYEOH-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- XQXPVVBIMDBYFF-UHFFFAOYSA-N 4-hydroxyphenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C=C1 XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 description 2
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- PLPCIGCUDCHUFB-UHFFFAOYSA-N tri(propan-2-yl)-[tri(propan-2-yl)silyloxymethoxymethoxy]silane Chemical class CC(C)[Si](C(C)C)(C(C)C)OCOCO[Si](C(C)C)(C(C)C)C(C)C PLPCIGCUDCHUFB-UHFFFAOYSA-N 0.000 description 1
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- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/48—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
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- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
- C07D273/01—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having one nitrogen atom
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present disclosure relates to novel, safe and efficient processes for the synthesis of Pimavanserin and salts thereof, as well as novel intermediates that can be used in these processes.
- Pimavanserin tartrate 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea L-hemi-tartrate, has the following chemical structure:
- Pimavanserin tartrate was developed by Acadia Pharmaceuticals and was approved under the trade name NUPLAZID® for use in patients with Parkinson's disease psychosis.
- Pimavanserin free base and its synthesis are disclosed in U.S. Pat. No. 7,601,740 (referred to herein as US '740 or the '740 patent) and U.S. Pat. No. 7,790,899 (referred to herein as US '899 or the '899 patent).
- US '740 discloses the synthesis of Pimavanserin free base (also referred to herein as “Compound A”), which includes O-alkylation followed by ester hydrolysis, and then in situ azidation. This process suffers from low process safety, and utilizes the hazardous reagent diphenylphosphoryl azide. The process is illustrated by the following Scheme 1.
- Both of the above processes for the preparation of Pimavanserin include a reaction between 1-isobutoxy-4-(isocyanatomethyl)benzene, a benzyl isocyanate intermediate, and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine.
- Processes for preparing benzyl isocyanate derivatives are generally described in the literature, such as in US '740; US '899; Bioorganic & Medicinal Chemistry, 21(11), 2960-2967, 2013; JP 2013087107; Synthesis (12), 1955-1958, 2005; and Turkish Journal of Chemistry, 31(1), 35-43, 2007. These processes often use the hazardous reagents like phosgene derivatives or diphenylphosphoryl azide.
- the present disclosure relates to novel, safe and efficient processes and intermediates for the synthesis of Pimavanserin and salts thereof. Coupling of carbamate derivatives to amines are typically performed using secondary amines. It was surprisingly found that such a reaction for the preparation of Pimavanserin failed to produce the desired compound, while a reaction with a primary amine intermediate provided the desired compound with great efficiency and quality.
- the present disclosure relates to a process for preparing the compound of formula XVII
- R 1 is a 2-methylpropan-oxy (“isobutoxy”) group or a group that can be converted into an isobutoxy group, or a salt thereof, with 1,1′-carbonyldiimidazole (CDI).
- isobutoxy 2-methylpropan-oxy (“isobutoxy”) group or a group that can be converted into an isobutoxy group, or a salt thereof, with 1,1′-carbonyldiimidazole (CDI).
- the present disclosure relates to the compound of formula XVII:
- the present disclosure also relates to the use of the compound of formula XVII in the preparation of Pimavanserin or a salt thereof.
- the present disclosure further provides a process comprising reacting the compound of formula XVII with a compound of formula V.
- the present disclosure provides a process for preparing the compound of formula Z
- R 1 is a 2-methylpropan-oxy (“isobutoxy”) group or a group that can be converted into an isobutoxy group, or a salt thereof, with 4-nitrophenyl chloroformate.
- the present disclosure also relates to the compound of formula Z:
- R 1 is as defined above.
- the compound of formula Z may also be employed as a useful intermediate in the synthesis of Pimavanserin or a salt thereof.
- the present disclosure provides a process comprising reacting the compound of formula Z with a compound of formula V
- the present disclosure also relates to the compound of the formula XVIII:
- R 1 is a 2-methylpropan-oxy (“isobutoxy”) group or a group that can be converted into an isobutoxy group.
- the compounds of formula XVIII and formula XIX, respectively, may likewise be employed as useful intermediates in the synthesis of Pimavanserin or a salt thereof.
- Another aspect of the present disclosure relates to the use of the compound of formula XVIII or the compound of formula XIX in the preparation of Pimavanserin or salts thereof.
- the present disclosure relates to a process comprising reacting a compound of formula XVIII
- FIG. 1 shows an x-ray powder diffractogram (“PXRD” or “XRPD”) of crystalline form I of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine dihydrochloride (Compound V ⁇ 2 HCl).
- FIG. 2 shows a PXRD of crystalline form II of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine dihydrochloride (Compound V ⁇ 2 HCl).
- FIG. 3 shows a PXRD of crystalline form I of (4-isobutoxyphenyl)methanamine hydrochloride (Compound XI ⁇ HCl).
- FIG. 4 shows a PXRD pattern of compound XVIII in a crystalline form I.
- FIG. 5 shows a PXRD of compound XVIII in a crystalline form II.
- FIG. 6 shows a PXRD of crystalline Pimavanserin form X.
- isolated corresponds to compounds that are physically separated from the reaction mixture in which they are formed.
- the processes or steps may be referred to herein as being carried out “overnight.” This refers to time intervals, e.g., for the processes or steps, that span the time during the night, when the processes or steps may not be actively observed.
- the time intervals are from about 8 to about 20 hours, or about 10-18 hours, or about 16 hours.
- reduced pressure refers to a pressure of about 10 mbar to about 500 mbar, or about 50 mbar.
- a thing e.g., a reaction mixture
- room temperature or “ambient temperature”, often abbreviated as “RT”. This means that the temperature of the thing is close to, or the same as that of the space, e.g., the room or fume hood, in which the thing is located.
- room temperature is from about 20° C. to about 30° C., or about 22° C. to about 27° C., or about 25° C.
- the amount of solvent employed in chemical processes, e.g., reactions or crystallizations, may be referred to herein as a number of “volumes” or “vol” or “V.”
- a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent.
- this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent.
- the term “v/v” may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume.
- Alkyl refers to a monoradical of a branched or unbranched saturated hydrocarbon chain. Examples include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, sec-butyl, isobutyl, etc. Alkyl groups typically contain 1-10 carbon atoms, such as 1-6 carbon atoms or 1-4 carbon atoms, and can be substituted or unsubstituted.
- Alkyloxy refers to a linear or branched, hydrocarbon group of formula —O-alkyl, in which the term “alkyl” is defined supra, and may include, e.g., a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof.
- Aryl refers to phenyl and 7-15 membered monoradical bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic.
- Aryl groups can be substituted or unsubstituted. Examples include, but are not limited to, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthalenyl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, and 6,7,8,9-tetrahydro-5H-benzocycloheptenyl.
- An aryl group may contain 6 (i.e., phenyl) or 9 to 15 ring atoms, such as 6 (i.e., phenyl) or 9-11 ring atoms, e.g., 6 (i.e., phenyl), 9 or 10 ring atoms.
- Alkylaryl refers to an alkyl group in which a hydrogen atom is replaced by an aryl group, wherein alkyl group and aryl group are defined supra. Alkylaryl groups can be substituted or unsubstituted. Examples include, but are not limited to, benzyl (C 6 H 5 CH 2 —).
- Alcohol protecting groups refers to protecting groups which are introduced into a molecule by chemical modification of hydroxyl groups, for example to obtain chemoselectivity in a subsequent reaction.
- the term and use of protecting groups is well known in the art and for example described in Philipp J. Kocie ⁇ ski: Protecting Groups, 1. Auflage, Georg Thieme Verlag, Stuttgart 1994; Peter G. M. Wuts, Theodora W. Greene: Green's Protective Groups in Organic Synthesis , Fifth Ed. John Wiley & Sons Inc., Hoboken, N.J.
- Alcohol protecting groups can be for example acetoxy groups, benzoyl groups (Bz), benzyl groups (Bn), ⁇ -methoxyethoxymethyl ether (MEM), [bis-(4-methoxyphenyl)phenylmethyl] (DMT), methoxymethyl ether (MOM), [(4-methoxyphenyl)diphenylmethyl], (MMT), p-methoxybenzyl ether (PMB), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP), triphenylmethyl (Tr), silyl ethers, trimethylsilyl ethers (TMS), triethylsilyl ethers (TES), tert-butyldimethylsilyl ethers (TBDMS), tri-iso-propylsilyloxymethyl ethers (TOM), triisopropylsilyl (TIPS) ethers, methyl ethers and e
- a solid state form such as a crystal form or amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure.
- Such data include, for example, powder X-ray diffractograms and solid state NMR spectra.
- the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone.
- a crystal form of a Pimavanserin or Pimavanserin intermediate, such as Compound 1, referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Pimavanserin or Pimavanserin intermediate, such as Compound 1, characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
- the XRPD measurements were taken using a CuK ⁇ radiation wavelength of 1.54184 ⁇ .
- wet crystalline form or “wet form” refer to a polymorph that was not dried using any conventional techniques to remove residual solvent. Examples for such conventional techniques can be, but not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow etc.
- dry crystalline form or “dry form” refer to a polymorph that was dried using any conventional techniques to remove residual solvent. Examples for such conventional techniques can be, but not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow etc.
- crystalline Pimavanserin form Y As used herein, the term “crystalline Pimavanserin form Y”, “form alpha” or “Pimavanserin form alpha” refers to the crystalline from alpha as described in U.S. Pat. No. 7,868,176.
- Pimavanserin is a drug typically used for the treatment of patients with Parkinson's disease psychosis.
- Salts of Pimavanserin can for example be formed with an acid wherein the corresponding base is an anion.
- Exemplary anions include, but are not limited to tartrate, hemi-tartrate, phosphate, sulphate, nitrate, diphosphate, bicarbonate, carbonate, clavulanate, isothionate, borate, halide, nitrate, acetate, succinate, lactate, lactobionate, laurate, mandelate, malate, citrate, fumarate, maleate, oleate, oxalate, ascorbate, nicotinate, benzoate, mesylate, salicylate, stearate, tannate, tosylate, valerate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluensulfonate, 2-ethane disulfonate, or naphthalenesul
- Salts of Pimavanserin are preferably pharmaceutically acceptable salts.
- pharmaceutically acceptable salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
- Pharmaceutical acceptable salts can be obtained by reacting Pimavanserin with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, phosphoric acid and the like.
- Pharmaceutically acceptable salts may also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example tartaric, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid.
- an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example tartaric, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid.
- a particularly preferred salt of Pimavanserin is the hemi-tartrate salt as this is
- the present disclosure also relates to certain compounds useful as intermediates in the synthesis of Pimavanserin.
- Such intermediates may employed either in their free base (or free acid) form, or in the form of their acid addition salts (in case of a basic group such as an amino group being present), or in the form of their base addition salts (in case an acidic functional group is present), with the possible choices including the examples listed above.
- the present disclosure relates to a process for preparing a compound of the following formula XVII.
- R 1 is a 2-methylpropan-oxy (“isobutoxy”) group or a group that can be converted into an isobutoxy group. Suitable groups that can be converted into an isobutoxy group are apparent to those of skill in the art and include, for example, a hydroxyl group, a halogen, a mesylate or triflate group, or an alcohol protecting group. In certain embodiments, R 1 may be a halogen, a silyl ether or an alkoxy group. Preferably, R 1 is an isobutoxy group resulting in a compound of formula VI-a:
- a compound of formula XI or a salt thereof, such as a hydrochloric acid addition salt
- CDI 1,1′-carbonyldiimidazole
- This process may generally be performed in the presence of suitable organic solvent, such as dimethylformamide (DMF), acetonitrile, N-methyl-2-pyrrolidone (NMP), dimethylformamide (DMA), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-Me-THF), toluene or mixtures thereof.
- suitable organic solvent such as dimethylformamide (DMF), acetonitrile, N-methyl-2-pyrrolidone (NMP), dimethylformamide (DMA), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-Me-THF), toluene or mixtures thereof.
- the solvent may be DMF, acetonitrile, toluene or a mixture thereof.
- Compound XVII may in some embodiments be isolated prior to the reaction with Compound V or a salt thereof, while in other embodiments, Compound XVII is used without isolation directly in the next step, i.e. in a “one-pot” reaction, with Compound V, or a salt thereof, to obtain Pimavanserin or the corresponding precursor of Pimavanserin, wherein R 1 is a group that is converted into an isobutoxy group in a subsequent step.
- the intermediate compound of formula XVII may be converted to Pimavanserin or salts thereof by a process comprising reacting Compound XVII with Compound V, or a salt thereof, as illustrated by Scheme 4 (in Scheme 4 below, R 1 in formula XVII is isobutoxy, i.e. compound of formula VI-a, although the same reaction can of course also be carried out with other R 1 substituents that may later be converted to an isobutoxy group).
- reaction depicted in Scheme 4 can be carried out in a suitable organic solvent such as acetone at rather mild conditions (e.g. 40-50° C.). If necessary, the R 1 substituent may subsequently be converted to an isobutoxy group to obtain Pimavanserin or a salt thereof.
- a suitable organic solvent such as acetone at rather mild conditions (e.g. 40-50° C.). If necessary, the R 1 substituent may subsequently be converted to an isobutoxy group to obtain Pimavanserin or a salt thereof.
- This reaction may be carried out in a suitable organic solvent such as THF in the presence of a base, for example triethylamine, methylamine, N,N-diisopropylethylamine (“DIPEA”), 4-Dimethylaminopyridine (DMAP), potassium carbonate, sodium carbonate, cesium carbonate, or mixtures thereof.
- a base for example triethylamine, methylamine, N,N-diisopropylethylamine (“DIPEA”), 4-Dimethylaminopyridine (DMAP), potassium carbonate, sodium carbonate, cesium carbonate, or mixtures thereof.
- DIPEA N,N-diisopropylethylamine
- DMAP 4-Dimethylaminopyridine
- potassium carbonate sodium carbonate
- cesium carbonate cesium carbonate
- R 1 may in some embodiments be a 2-methylpropan-oxy (“isobutoxy”) group, or a group that can be converted into an isobutoxy group.
- R 1 is an isobutoxy group resulting in a compound of formula Y:
- the conversion of compound of formula Z (or compound of formula Y) to Pimavanserin (or a precursor of Pimavanserin wherein R 1 is converted into an isobutoxy group in a subsequent step), or a salt thereof, may be accomplished by a process that comprises reacting Compound Z (or Y) with a compound V as illustrated by Scheme 7 below (shown with the specific example Compound Y).
- the reaction may be carried out in a suitable organic solvent, such as acetonitrile, and preferably includes a base, e.g. DMAP, as described for the analogous reaction of the compound of formula XVII with the compound of formula V.
- a suitable organic solvent such as acetonitrile
- a base e.g. DMAP
- the residue R 1 may subsequently be converted to an isobutoxy group to obtain Pimavanserin, or a salt thereof.
- the obtained Pimavanserin is further converted to the Pimavanserin hemi-tartrate salt.
- the 4-substituted benzylamine of formula XI-a may conveniently be prepared by converting a compound of formula XIII-a
- the starting compound of formula XIII may in turn be obtained by reacting the 4-hydroxy-substituted precursor with isobutyl bromide in the presence of a base and catalytic amounts of potassium iodide (KI) in a suitable organic solvent such as DMF.
- KI potassium iodide
- the present disclosure also includes the compound of formula XI as a hydrochloride salt in a crystalline form.
- the crystalline form, designated Form I can be characterized by data selected from one or more of the following: X-ray powder diffraction pattern having peaks at about 3.9, 7.8, 11.7, 19.5 and 22.8 degrees two theta ⁇ 0.2 degrees two theta; an X-ray powder diffraction pattern as depicted in FIG. 3 ; and combinations of this data.
- Crystalline Form I of Compound XI HCl can be further characterized by an X-ray powder diffraction pattern having peaks at 3.9, 7.8, 11.7, 19.5 and 22.8 degrees two theta ⁇ 0.2 degrees two theta and also having any one, any two, any three or more additional peaks selected from the group consisting of 15.6, 18.1, 20.5, 23.4 and 27.4 degrees two theta ⁇ 0.2 degrees two theta.
- the disclosure further relates to a process which utilizes a hydroxamic acid derivative as an intermediate for producing Pimavanserin.
- Hydroxamic acid is known from U.S. Pat. No. 3,479,396; and reactions for the conversion of hydroxamic acid derivative to isocyanates are known from P. Dube et al. Org. Lett., Vol. 11, No. 24, 2009, 5622; or Zhao et al. Org. Process Res. Dev 2 Apr. 2015 (Web).
- the present disclosure also relates to a novel N-hydroxy-2-(4-substituted)phenyl acetamide of the general formula XVIII:
- R 1 is as defined above, i.e. a 2-methylpropan-oxy (“isobutoxy”) group or a group that can be converted into an isobutoxy group.
- R 1 is an isobutoxy group, and the resulting compound N-hydroxy-2-(4-isobutoxyphenyl)acetamide is referred to herein as “Compound 1”.
- R 1 is as defined above (preferably wherein R 1 is isobutoxy), and wherein R 2 may be alkyl, aryl or hydrogen.
- R 2 is C 1 -C 6 alkyl, such as methyl or ethyl, or phenyl, or hydrogen.
- Compound B may be converted into a compound of formula XVIII.
- Compound B is reacted with hydroxylamine or hydroxylamine hydrochloride, in the presence of CDI, and a suitable solvent.
- R 1 is isobutoxy and R 2 is hydrogen.
- the solvent is an organic solvent such as acetonitrile, tetrahydrofuran (THF) or methyl-tetrahydrofuran (Me-THF), or mixtures thereof.
- the solvent is acetonitrile.
- the compound of formula XVIII can be prepared by hydroxylamination of methyl 2-(4-substituted phenyl)acetate. This reaction may be performed in the presence of hydroxylamine or hydroxylamine hydrochloride. In some embodiments, the hydroxylamination is performed in the presence of a base.
- the base is an inorganic base, such as sodium methoxide, potassium methoxide, potassium carbonate, sodium hydroxide or potassium hydroxide, or a mixture thereof and in the presence of a solvent.
- the solvent is an organic solvent, such as methanol, DMF, THF or Me-THF or a mixture thereof. Most preferably, the solvent is methanol.
- the present inventors found that the compound of formula XVIII, such as Compound 1, is a useful intermediate for making Pimavanserin or a salt thereof.
- the use of Compound XVIII (or Compound 1) in the preparation of Pimavanserin, or a salt thereof represents another aspect of the present disclosure.
- Compound XVIII can be used either in an isolated form or prepared in situ, i.e. in a one-pot reaction. When used in isolated form, it may be in a crystalline form.
- the present disclosure also includes Compound 1 (Compound XVIII with R 1 being isobutoxy-) in a crystalline form, designated form I, characterized by data selected from one or more of the following: an X-ray powder diffraction pattern having peaks at about 4.0, 11.9, 16.8, 17.7 and 19.8° 2 ⁇ 0.2° 2 ⁇ ; an X-ray powder diffraction pattern as depicted in FIG. 1 ; and combinations of this data.
- Compound 1 Compound XVIII with R 1 being isobutoxy-
- form I characterized by data selected from one or more of the following: an X-ray powder diffraction pattern having peaks at about 4.0, 11.9, 16.8, 17.7 and 19.8° 2 ⁇ 0.2° 2 ⁇ ; an X-ray powder diffraction pattern as depicted in FIG. 1 ; and combinations of this data.
- Crystalline form I of Compound 1 may be further characterized by an X-ray powder diffraction pattern having peaks at 4.0, 11.9, 16.8, 17.7 and 19.8° 2 ⁇ 0.2° 2 ⁇ and also having any one, any two, any three additional peaks selected from 7.9, 15.8 and 23.0° 2 ⁇ 0.2° 2 ⁇ .
- Crystalline form I of Compound 1 may be characterized by each of the above characteristics alone and/or by all possible combinations.
- Compound 1 in another crystalline form, designated form II, is another embodiment and can be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern having peaks at about 3.9, 7.8, 11.6, 15.5 and 23.4° ⁇ 0 ⁇ 0.2° 2 ⁇ ; an X-ray powder diffraction pattern as depicted in FIG. 2 ; and combinations of this data.
- Crystalline form II of Compound 1 can be further characterized by an X-ray powder diffraction pattern having peaks at 3.9, 7.8, 11.6, 15.5 and 23.4° 2 ⁇ 0.2° 2 ⁇ and also having any one, any two, any three or more additional peaks selected from 16.4, 20.7, 22.5, 26.5 and 31.7° ⁇ 0 ⁇ 0.2° 2 ⁇ .
- Crystalline form II of Compound 1 may be characterized by each of the above characteristics alone and/or by all possible combinations.
- the compound of formula XVIII (such as Compound 1) can be converted to Pimavanserin, or a salt thereof, by reacting it with CDI to obtain an intermediate of formula XIX (as shown below) which is then converted to Pimavanserin (or the respective derivative where R 1 is only converted to isobutoxy in a subsequent step), or a salt thereof.
- the process comprises
- step a) is performed in the presence of a solvent.
- Suitable solvents include for example acetonitrile, tetrahydrofuran (THF) or methyl-tetrahydrofuran (Me-THF), or mixtures thereof.
- the solvent is acetonitrile.
- the above reaction may be performed at a temperature of from about 20° C. to about 80° C.
- the temperature is about 50° C. to about 70° C. More preferably, the temperature is about 60° C. to about 65° C.
- R 1 may be a 2-methylpropan-oxy (“isobutoxy”) group or a group that can be converted into an isobutoxy group.
- R 1 is an isobutoxy group
- the compound of formula XIX is referred to herein as Compound 2 (5-((4-isobutoxy)-benzyl)-1,3,4-dioxazol-2-one):
- the intermediate of formula XIX (such as Compound 2) can be used in the preparation of Pimavanserin, or a salt thereof, which therefore represents yet another aspect of the present disclosure.
- the intermediate of formula XIX/Compound 2 may be isolated before reacting it with the compound of formula V.
- the reaction is performed without the isolation of the intermediate of formula XIX/Compound 2, i.e. as a one-pot reaction.
- Compound V can be prepared according to US '740, or, alternatively, by reacting 4-fluorobenzaldehyde (referred to herein as compound of formula III) and 1-methylpiperidin-4-amine (referred to herein as compound of formula IV) in the presence of a reducing agent, as illustrated by Scheme 11:
- the processes for preparing Pimavanserin, or a salt thereof include the step of preparing compound of formula V via the compounds of formula III and IV.
- the isobutoxy substituent in position R 1 present in many compounds disclosed herein can for example be created by reacting (an optionally protected/derivatized) phenolic hydroxyl group with an alkylation agent, for example, 1-bromo-2-methylpropane, 1-iodo-2-methylpropane, or 1-chloro-2-methylpropane.
- an alkylation agent for example, 1-bromo-2-methylpropane, 1-iodo-2-methylpropane, or 1-chloro-2-methylpropane.
- the alkylation agent for this reaction step is 1-bromo-2-methylpropane.
- the alkylation may be performed in the presence of a base.
- the base is an inorganic base. More preferably, the base is potassium carbonate, sodium carbonate, or cesium carbonate, or a mixture thereof. Most preferably, the base is potassium carbonate.
- this reaction may be performed in the presence of a solvent.
- the solvent is a polar solvent. More preferably, the solvent is dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMA) or dimethyl sulfoxide (DMSO). Most preferably, the solvent is DMF.
- Pimavanserin may be obtained in a crystalline form.
- the present disclosure includes crystalline Pimavanserin designated form X, characterized by data selected from one or more of the following: X-ray powder diffraction pattern having peaks at about 5.1, 5.4, 9.1, 9.7 and 16.6° 2 ⁇ 0.2° 2 ⁇ ; an X-ray powder diffraction pattern as depicted in FIG. 3 ; and combinations of this data.
- Crystalline Pimavanserin form X may be further characterized by the X-ray powder diffraction pattern having peaks at 5.1, 5.4, 9.1, 9.7 and 16.6° 2 ⁇ 0.2° 2 ⁇ and also having any one, any two, any three additional peaks selected from 17.8, 18.2, 18.6, 20.2 and 21.5° 2 ⁇ 0.2° 2 ⁇ .
- Crystalline Pimavanserin form X may be characterized by each of the above characteristics alone and/or by all possible combinations. Form X may for example be obtained according to the procedure outlined in Example 35.
- the obtained Pimavanserin may be further converted to a salt, preferably, a pharmaceutically acceptable salt.
- a salt preferably, a pharmaceutically acceptable salt.
- Pimavanserin may be converted to its hemi-tartrate salt. The conversion can be done either directly, i.e. in a one-pot manner, or with isolation of Pimavanserin prior to the conversion into the respective salt.
- the present disclosure also describes the use of tetraalkylammonium isocyanate in the preparation of Pimavanserin and salts thereof.
- R 1 , R 2 , R 3 and R 4 can be the same or different, and, independently, may be an alkyl, aryl or alkyl-aryl.
- R 1 , R 2 , R 3 , and R 4 are, independently, alkyl.
- R 1 , R 2 , R 3 , and R 4 are, independently, C 1 -C 6 alkyl.
- R 1 , R 2 , R 3 , and R 4 are, independently, C 4 alkyl.
- R 1 , R 2 , R 3 , and R 4 are, independently, n-butyl.
- R 1 , R 2 , R 3 and R 4 are as defined above, with compound (A) being Pimavanserin.
- the compound of formula VI may be employed as a useful intermediate in the synthesis of Pimavanserin or a salt thereof. Such a process involves reacting the compound of formula VI with a compound of formula XI-a
- R 1 is a 2-methylpropan-oxy (“isobutoxy”) group or a group that can be converted into an isobutoxy group, to obtain Pimavanserin or a salt thereof.
- R 1 is isobutoxy (referred herein as a compound of formula XI).
- the compound of formula XI-a (such as XI) may be first converted to a salt, such as a hydrochloric acid addition salt, before reacting it with Compound VI.
- the compound of formula VI itself may be prepared by a process comprising reacting N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (Compound of formula V) and 1,1′-carbonyldiimidazole (“CDI”), as illustrated by Scheme 16 below.
- reaction illustrated by Scheme 16 may be carried out in a polar solvent such as acetone, optionally in the presence of some additional imidazole and/or imidazole hydrochloride.
- a polar solvent such as acetone
- the sample after being carefully powdered in a mortar and pestle, is applied directly on a silicon plate holder.
- the X-ray powder diffraction pattern was measured with a Philips X′Pert PRO X-ray powder diffractometer, equipped with Cu K ⁇ irradiation source (wavelength 1.54184 ⁇ ) and X'Celerator (2.022° 2 ⁇ ) detector. Scanning parameters: angle range: 3-40°, step size 0.0167, time per step 37 s, continuous scan.
- the batch was cooled down to room temperature and diluted with 100 mL of DI water (20 vol.).
- the product precipitated, and collected by vacuum filtration.
- the filter cake was washed with 50 mL of DI water (10 vol), and dried in the Buchner funnel with nitrogen sweep for 1 hour before transferring into vacuum oven, drying at 80° C. under full house vacuum for 20 hours. This afforded 5.147 g of 4-isobutoxybenzamide as a white solid, representing a 93.6% yield in 99.8 A % purity.
- the batch was cooled down to room temperature and quenched by charging 20 mL of saturated NH 4 Cl aqueous solution.
- the resultant reaction mixture was concentrated under vacuum to remove the organic solvent.
- the residue was diluted with 200 mL of ethyl acetate, and extracted with 3 ⁇ 60 mL of 1N HCl aqueous solution.
- the combined aqueous layers were basified with 50 mL of ammonium hydroxide aqueous solution, and back-extracted with 2 ⁇ 50 mL of methylene chloride. After partition, the organic layer was concentrated to dryness to afford 1.432 g of Compound XI as hemi-solidified liquid, representing a 66% yield in 98.6 A % purity.
- the above reaction mixture was charged into the other 25 mL seal tube containing 489.1 mg of Compound V (FW: 222.3, 2.2 mmol, 1.1 equiv.). After sealing the tube, the reaction mixture was heated to 60° C. The batch was stirred at the same temperature for additional 2 hours until HPLC indicated a complete reaction. The reaction mixture was cooled to room temperature, and concentrated to dryness in vacuo. The residue was dissolved in 5 mL of iPrOAc, washed with 5 mL of DI water. After partition, the product was in upper organic layer, which was washed with additional 5 mL of DI water. The resultant organic layer was concentrated again to dryness.
- Example 20 Comparative Example: Coupling of Carbamate Derivative to a Secondary Amine
- Step 2 Synthesis of Pimavanserin by Coupling Between 4-nitrophenyl 4-fluorobenzyl(1-methylpiperidin-4-yl)carbamate and Compound XI
- Step 4 Synthesis of Pimavanserin by Coupling Between Compound VI and Compound XI
- the reaction was performed in 300 mL reactor.
- the reactor was purged with N 2 , then Argon.
- 4-Fluorobenzylamine (10 g; 80 mmol, 1.0 eq) was dissolved in dry MeCN (100 mL), then 1-methylpiperidin-4-one (10.9 g; 96 mmol, 1.2 eq) was added and the reaction mixture was stirred at ambient temperature for 18 h.
- the reaction mixture was cooled to 0° C. and 25.4 g of NaBH(OAc) 3 (25.4 g; 120 mmol, 1.5 eq) was added in portions over 20 min and the reaction was allowed to stir to room temperature.
- N-(4-fluorobenzyl)-1-methylpiperidin-4-amine 10 g; 0.045 mol
- DCM 50 mL
- 5-6 N HCl in 2-PrOH 3 equiv., 0.135 mmol
- Step 4 Option 1: Preparation of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea (Pimavanserin
- Step 4 Option 2: Preparation of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea (Pimavanserin)
- the reaction was performed in 250 mL, three necked, round bottom flask. 4-Fluorobenzylamine (11.010 g; 88 mmol, 1.0 eq) was dissolved in dry MeCN (110 mL), 1-methylpiperidin-4-one (10.5 g; 92 mmol, 1.05 eq) was added and the reaction mixture was stirred at ambient temperature for 16 h. Then, the reaction mixture was cooled to 0° C., NaBH(OAc) 3 (29.8 g; 140 mmol, 1.6 eq) was added and the reaction mixture was allowed to stir to room temperature.
- 4-Fluorobenzylamine (11.010 g; 88 mmol, 1.0 eq) was dissolved in dry MeCN (110 mL), 1-methylpiperidin-4-one (10.5 g; 92 mmol, 1.05 eq) was added and the reaction mixture was stirred at ambient temperature for 16 h. Then, the reaction mixture was cooled to
- N-(4-fluorobenzyl)-1-methylpiperidin-4-amine 17.01 g; 0.077 mol
- ethyl acetate 170 mL
- 5-6 N HCl in 2-PrOH 3.4 equiv., 0.264 mol
- the reaction was performed in 250 mL, three necked, round bottom flask. 4-Fluorobenzylamine (11.010 g; 88 mmol, 1.0 eq) was dissolved in dry MeCN (110 mL), 1-methylpiperidin-4-one (10.5 g; 92 mmol, 1.05 eq) was added and the reaction mixture was stirred at ambient temperature for 16 h. Then, the reaction mixture was cooled to 0° C., NaBH(OAc) 3 (29.8 g; 140 mmol, 1.6 eq) was added and the reaction mixture was allowed to stir to room temperature.
- 4-Fluorobenzylamine (11.010 g; 88 mmol, 1.0 eq) was dissolved in dry MeCN (110 mL), 1-methylpiperidin-4-one (10.5 g; 92 mmol, 1.05 eq) was added and the reaction mixture was stirred at ambient temperature for 16 h. Then, the reaction mixture was cooled to
- N-(4-fluorobenzyl)-1-methylpiperidin-4-amine 17.52 g; 0.079 mol
- DCM 100 mL
- 5-6 N HCl in 2-PrOH 3.3 equiv., 0.264 mol
- the reaction was performed in a 250 mL, three necked, round bottom flask. 4-Fluorobenzylamine (11.010 g; 88 mmol, 1.0 eq) was dissolved in dry MeCN (110 mL), 1-methylpiperidin-4-one (10.5 g; 92 mmol, 1.05 eq) was added and the reaction mixture was stirred at 40° C. for 16 h. Then, the reaction mixture was cooled to 0° C., NaBH(OAc) 3 (29.8 g; 140 mmol, 1.6 eq) was added and the reaction mixture was allowed to stir to room temperature.
- 4-Fluorobenzylamine (11.010 g; 88 mmol, 1.0 eq) was dissolved in dry MeCN (110 mL), 1-methylpiperidin-4-one (10.5 g; 92 mmol, 1.05 eq) was added and the reaction mixture was stirred at 40° C. for 16 h. Then, the
- N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (16.83 g; 0.076 mol) and DCM (100 mL) were charged and cooled to 10-15° C.
- 4.395 N HCl in 2-PrOH 3.5 equiv., 0.264 mol was added dropwise over 25 min, white crystals was formed, and the solution then cooled to 0-5° C. for 2 hours.
- the reaction was performed in a 1000 mL reactor. N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (100 g, 0.45 mol) and DCM (500 mL) were charged and cooled to 10-15° C. To the resulting solution, 5-6 N HCl in 2-PrOH (3 equiv., 1.35 mol) was added dropwise over 25 min, white crystals was formed, and the solution then cooled to 0-5° C. for 2 hours.
- the batch was diluted with 6 mL of acetonitrile (6 vol.) and 16 mL (16 vol.) of DI water, and cooled down to 0-5° C. After stirring at the same temperature for additional 1 hour, the batch was filtered on the Buchner funnel. The filter cake was washed with 2 ⁇ 10 mL (10 vol.) of DI water, and dried in the funnel under vacuum overnight to afford 774.1 mg of hydroxamic acid Compound 1, representing a 72% yield in 99.6 A % purity.
- the reaction was monitored by HPLC and complete in 2 hours.
- the batch was cooled down to room temperature, diluted with 5 mL (20 vol.) of ethyl acetate, which was washed with 3 ⁇ 5 mL (20 vol.) of DI water. After partitioning, the upper organic layer was concentrated to dryness on rotary evaporator. The residue was re-dissolved into 3 mL (12 vol.) of ethyl acetate after heating up to reflux to afford a slightly milky solution. This was charged with 12 mL (48 vol.) of heptane, and cooled down to 0-5° C. The batch was kept stirring at the same temperature for 1 hour and filtered on a Buchner funnel.
- the reaction was performed in a 300 mL reactor.
- the reactor was purged with N 2 , then Ar.
- 10 g of 4-fluorobenzylamine (FW: 125.14, 79.91 mmol, 1.0 equiv) was dissolved in 100 ml of dry MeCN (10 vol.), then 1-methylpiperidin-4-one (FW: 113.16, 95.97 mmol, 1.2 equiv) was added and the reaction mixture was stirred at ambient temperature for 18 h.
- the reaction mixture was cooled to 0° C., and 25.4 g of NaBH(OAc) 3 (FW: 119.85 mmol, 1.5 equiv) was added in portions over 20 min.
- the reaction was allowed to stir to room temperature.
- reaction mixture was divided and worked-up using two different routes.
- the reaction mixture was diluted with EtOAc (20 mL) and washed twice with a saturated solution of NH 4 Cl (2 ⁇ 15 mL), then with a saturated NaCl solution (10 mL). The organic layer was dried over anh. Na 2 SO 4 , filtered and evaporated to 5 mL. The solution was stirred at ambient temperature and n-heptane (10 mL) was added dropwise. White precipitate was formed, filtered off, washed with n-heptane and dried at 45° C. in vacuum for 3 h, yielding 0.251 g of Pimavanserin (form Y), HPLC purity 98 area %.
- the reaction mixture was diluted with EtOAc (20 mL) and washed three times with 0.1 M HCl (3 ⁇ 15 mL), following with a saturated NaCl solution (10 mL). The organic layer was dried over anh. Na 2 SO 4 , filtered and evaporated to 5 mL. The solution was stirred at 60° C. and n-heptane (15 mL) was added dropwise. An oil was first formed, followed by a white precipitate. The temperature was gradually lowered over 3 h, and left to stir overnight. The precipitate was filtered off, washed with n-heptane and dried at 45° C. in vacuum for 3 h, yielding 0.094 g of precipitate HPLC purity 95.3 area %. From the mother liquid, after filtration, washing and drying, 0.046 g of precipitate (form X) was observed, HPLC purity 97.6 area %.
- Reduction of the resulting imine was performed in a 250 mL reactor. Reactor was purged with N 2 and NaBH(OAc) 3 (29.84 g, 0.14 mol) was suspended in MeCN (80 mL). The suspension was cooled to 0-5° C. and solution of the imine in MeCN was added dropwise during 20 min. After the addition was completed, temperature was increased to 20° C. in 5° C. increments, during 1 h. After 2.5 h at 20° C., the reaction was quenched with addition of water (200 mL). Then DCM (100 mL) was added and pH was adjusted to 2 with 5M HCl solution.
- Reduction of the resulting imine was performed in a 500 mL three necked round bottom flask. The flask was purged with N 2 and NaBH 4 (5.32 g, 0.14 mol) was suspended in MeCN (50 mL). The suspension was cooled to 0-5° C. and solution of glacial acetic acid (24.1 mL, 0.42 mol) in MeCN (60 mL) was added dropwise over 60 minutes to give desired NaBH(OAc) 3 . The solution of the imine in MeCN was then added dropwise into the suspension of in situ prepared NaBH(OAc) 3 at 0-5° C., over 30 min. After the addition was completed, reaction mixture was stirred at 0-5° C.
- Reduction of the resulting imine was performed in a 600 mL autoclave with addition of Raney-Ni (3.3 g, 30 wt. %), glacial acetic acid (5.03 mL, 0.088 mol), MeOH (75 mL) and at 5 bar pressure for 66 h.
- the solution was concentrated to 50 mL and water (100 mL) and DCM (100 mL) were added. pH of this solution was adjusted to 2 with 5M HCl. Layers were separated and aqueous one washed with once again with DCM (100 mL), basified to pH 9.5 with 6M NaOH and extracted with DCM 2 ⁇ 100 mL.
- reaction solution was cooled to 20° C. and water was added dropwise in ratio 1:3 (300 mL) with adjustment of pH to 11 with 6N NaOH solution. After addition of whole amount of water, crystals were formed and suspension was stirred at 20° C. for 2 h and 0-5° C. for next 2 hour. Crystals were filtered off, washed with 2 ⁇ 100 mL solution of MeCN:H 2 O 1:3, then 100 mL of H 2 O, dried at 30° C./10 mbar for 24 hours yielding 17.56 g (91.7%) of Pimavanserin.
Abstract
Description
wherein R1 is a 2-methylpropan-oxy (“isobutoxy”) group or a group that can be converted into an isobutoxy group, or a salt thereof, with 1,1′-carbonyldiimidazole (CDI).
wherein R1 is as defined above. The compound of formula XVII may be employed as a useful intermediate in the synthesis of Pimavanserin or a salt thereof.
wherein R1 is a 2-methylpropan-oxy (“isobutoxy”) group or a group that can be converted into an isobutoxy group, or a salt thereof, with 4-nitrophenyl chloroformate.
wherein R1 is as defined above. The compound of formula Z may also be employed as a useful intermediate in the synthesis of Pimavanserin or a salt thereof.
wherein R1 is a 2-methylpropan-oxy (“isobutoxy”) group or a group that can be converted into an isobutoxy group. The compounds of formula XVIII and formula XIX, respectively, may likewise be employed as useful intermediates in the synthesis of Pimavanserin or a salt thereof.
wherein R1 is as defined above, with 1,1′-carbonyldiimidazole (CDI) to obtain a compound of formula XIX
or a salt thereof, with 1,1′-carbonyldiimidazole (CDI). R1 is a 2-methylpropan-oxy (“isobutoxy”) group or a group that can be converted into an isobutoxy group. Suitable groups that can be converted into an isobutoxy group are apparent to those of skill in the art and include, for example, a hydroxyl group, a halogen, a mesylate or triflate group, or an alcohol protecting group. In certain embodiments, R1 may be a halogen, a silyl ether or an alkoxy group. Preferably, R1 is an isobutoxy group resulting in a compound of formula VI-a:
wherein R1 is as defined above. This process step is illustrated in Scheme 6 (the Scheme depicts the reaction with compounds of formula XI and Y, respectively, i.e. with R1=isobutoxy, although it can of course also be carried out with other groups that may later be converted into an isobutoxy group.
is a useful intermediate in the synthesis of Pimavanserin or salts thereof, and thus represents another aspect of the present disclosure.
to said compound of formula XI-a, or a salt thereof, by reductive amination via catalytic hydrogenation, e.g. with Raney Nickel, methanolic ammonia solution under hydrogen atmosphere, optionally followed by conversion into its acid addition salt (e.g. with HCl).
wherein R1 is as defined above, i.e. a 2-methylpropan-oxy (“isobutoxy”) group or a group that can be converted into an isobutoxy group. Preferably, R1 is an isobutoxy group, and the resulting compound N-hydroxy-2-(4-isobutoxyphenyl)acetamide is referred to herein as “
wherein R1 is as defined above (preferably wherein R1 is isobutoxy), and wherein R2 may be alkyl, aryl or hydrogen. Preferably, R2 is C1-C6 alkyl, such as methyl or ethyl, or phenyl, or hydrogen.
wherein R1 is a 2-methylpropan-oxy (“isobutoxy”) group or a group that can be converted into an isobutoxy group, to obtain Pimavanserin or a salt thereof. Preferably, R1 is isobutoxy (referred herein as a compound of formula XI).
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EP3271018A1 (en) | 2018-01-24 |
US20190276401A1 (en) | 2019-09-12 |
WO2016141003A1 (en) | 2016-09-09 |
US10343993B2 (en) | 2019-07-09 |
US20180037549A1 (en) | 2018-02-08 |
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